General principles of neoadjuvant management of breast cancer

INTRODUCTION — Neoadjuvant therapy refers to the systemic treatment of breast cancer prior to definitive surgical therapy (ie, preoperative therapy). In the past, this almost always consisted of neoadjuvant chemotherapy (NACT), but, more recently, there has been increasing interest in assessing the role of neoadjuvant endocrine therapy, as well as targeted therapies, sometimes administered concurrent with, and sometimes in lieu of, chemotherapy, in certain subsets of patients.

This topic will review patient selection, pretreatment assessment, treatment options, and evaluation of response to and treatment after neoadjuvant therapy. Where clinical guidance is provided in this topic, the anatomic staging system set forth in the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual is used (table 1). Clinicians may also find it useful to refer to the clinical prognostic staging system set forth in the eighth edition AJCC manual, which incorporates prognostic features such as tumor grade and hormone and human epidermal growth factor receptor 2 (HER2) receptor status, and thus provides more refined prognostic information prior to surgery (table 2). Of note, the AJCC eighth edition does not have a pathologic staging system for patients treated with neoadjuvant therapy. Additionally, the studies cited in this topic typically used previous editions of the staging system to define and describe their patient populations, which is a limitation of available data. Further discussion of existing staging systems, including the clinical and pathologic prognostic staging systems, are found elsewhere (table 2 and table 3). (See "Tumor, node, metastasis (TNM) staging classification for breast cancer".)

Specific issues related to deciding between NACT versus neoadjuvant endocrine therapy in hormone receptor-positive/HER2-negative cancers, the role of HER2-directed therapies in HER2-positive cancers, selecting a NACT regimen, and the impact of response to neoadjuvant therapy on choice of postoperative therapy are discussed elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer" and "Neoadjuvant therapy for patients with HER2-positive breast cancer" and "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer" and "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer".)

GOALS — While all systemic therapy given for non-metastatic, invasive breast cancer is intended to reduce the risk of distant recurrence, the purpose of administering it prior to surgery is to downstage the extent of disease in the breast and/or regional lymph nodes and provide information regarding treatment response to direct adjuvant therapies. Downstaging may allow less extensive surgery on the breast and/or axilla, including avoiding the risks associated with breast reconstruction in patients able to undergo breast-conserving surgery in place of mastectomy, improving cosmetic outcomes, and reducing postoperative complications such as lymphedema [1-6]. Neoadjuvant therapy also permits evaluation of the effectiveness of systemic therapy, which is increasingly used to guide adjuvant treatment recommendations. The presence and extent or absence of residual invasive cancer after neoadjuvant therapy is a strong prognostic factor for risk of recurrence, especially in triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. (See 'Poor response to or progression on neoadjuvant therapy' below.)

In addition to these clinical objectives, neoadjuvant therapy gives researchers the opportunity to obtain imaging studies, tumor specimens, and blood samples prior to, during, and, in patients with sufficient residual disease at surgery, after the preoperative treatment, which may assist in the identification of tumor- or patient-specific biomarkers of response or resistance.

Although it was hypothesized that overall survival might be improved with neoadjuvant therapy, as it provides earlier initiation of systemic therapy in patients at higher risk of distant recurrence, randomized trials have demonstrated equivalent mortality for pre- or postoperative delivery of similar systemic therapy [1,3,7-15]. An individual patient data meta-analysis was conducted by the Early Breast Cancer Trialists' Collaborative Group based upon data from 4756 women in 10 trials that were initiated between 1983 and 2002 [16]. There were no significant differences between neoadjuvant chemotherapy (NACT) versus adjuvant chemotherapy in the risk of distant recurrence (15-year rate of 38 percent in both arms) or breast cancer mortality (34 percent in both arms). The use of NACT was associated with an increased frequency of breast-conserving therapy (65 versus 49 percent). It was also associated with an increased risk of local recurrence (15-year local recurrence rate, 21.4 versus 15.9 percent; rate ratio 1.37, 95% CI 1.17-1.61), which has been attributed to the increased use of breast-conserving surgery.

While there have been advances in selecting patients for neoadjuvant therapy, given recognition of the potential benefits of preoperative treatment on surgical management and selection of subsequent treatment based on response, it is unlikely that further large, randomized trials comparing neoadjuvant and adjuvant therapy will be conducted.

TERMINOLOGY — The discussion that follows uses both clinical and pathologic staging in management decisions. Particular notes regarding pathologic assessment are as follows:

●The American Joint Committee on Cancer and the International Union for Cancer Control Tumor, Node, Metastasis breast cancer staging system uses "y" to designate stage after neoadjuvant therapy, so clinical stage after neoadjuvant therapy is indicated by ycTN and pathologic stage by ypTN or ypTNM. The tumor (ypT) is measured as the largest single focus of residual invasive tumor, not including areas of fibrosis within the tumor bed.

●The most widely accepted definition of pathologic complete response requires the absence of residual invasive disease in the breast and the absence of measurable disease in any sampled axillary nodes (ypT0/is ypN0). In retrospective meta-analyses, the presence of residual in situ carcinoma did not affect risk of distant recurrence in patients with no residual invasive cancer. This is the definition used in the following discussion, unless otherwise indicated.

PATIENT SELECTION — While originally developed for patients with locally advanced breast cancer, in whom even mastectomy may not be an option, neoadjuvant therapy is now frequently administered to patients with operable breast cancers, in an effort to avoid mastectomy or improve cosmetic outcomes following surgery or to limit the extent of axillary lymph node removal. Additionally, it can be used to assess response to neoadjuvant therapy, even if unlikely to alter surgical approach, if this could influence selection of postoperative therapy [17]. Discussions between the breast surgical oncologist and medical oncologist, and often other specialists, including a radiation oncologist and plastic surgeon, if reconstruction is being considered, are vital in determining the goals and potential benefits of neoadjuvant therapy for a given patient. Potential indications are listed below.

●Locally advanced breast cancer – Patients with locally advanced breast cancer (those with stage III disease, T3, or T4 lesions (table 1)), no matter the subtype, are ideal candidates for neoadjuvant therapy because their cancers are often not amenable to upfront resection, much less breast conservation, and because their risk of distant recurrence warrants systemic treatment. Many patients with tumors larger than 5 cm (T3), even if potentially operable, are considered to have locally advanced disease and have been included in neoadjuvant therapy clinical trials. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer", section on 'Locally advanced breast cancer'.)

●Select patients with early-stage breast cancer – Patients with stage I or II breast cancer are appropriate candidates for neoadjuvant therapy if breast-conserving surgery is not possible due to a high tumor-to-breast ratio, or if their anticipated cosmetic outcome would be suboptimal due to tumor location.

Additionally, neoadjuvant therapy is often recommended to patients with T2 tumors and even T1c triple-negative or human epidermal growth factor receptor 2 (HER2)-positive breast cancers, in part to identify patients who might benefit from additional treatments in the adjuvant setting if a pathologic complete response (pCR) is not achieved [17]. Moreover, these patients would typically receive systemic therapy at some point in their treatment course, and these subtypes are associated with a high likelihood of clinical and pathologic response [18]. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'T-DM1' and "Neoadjuvant therapy for patients with HER2-positive breast cancer" and "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Chemotherapy' and "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer".)

The role of neoadjuvant therapy in patients with early-stage hormone receptor-positive, HER2-negative breast cancers is less clear. While chemotherapy in such cases infrequently yields a pCR [19-22], neoadjuvant treatment will often induce tumor shrinkage that may be sufficient to allow breast conservation in a patient who otherwise would have required mastectomy. Whether such patients should be offered neoadjuvant chemotherapy or neoadjuvant endocrine therapy depends on many factors, including patient age, comorbidities, and clinical stage. Tumor characteristics including grade and intensity of hormone-receptor expression may help differentiate between patients more or less likely to respond to chemotherapy versus endocrine therapy. Data suggest that tumor proliferation indices such as Ki-67 or gene expression assays (such as Oncotype Dx, MammaPrint, or EndoPredict) may help oncologists to select between treatment options in these patients. Further discussion of indications for neoadjuvant therapy for estrogen receptor-positive tumors is found elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)

●Limited clinically node-positive disease – Another possible indication for neoadjuvant therapy in patients with early-stage breast cancer, regardless of the size of the primary tumor, is to downstage the axillary nodes in patients with limited clinically node-positive disease (cN1). The standard surgical approach to patients with clinically node-positive breast cancer, whether the patient received neoadjuvant therapy or not, had been an axillary lymph node dissection, which is associated with higher rates of lymphedema and restricted mobility of the affected arm, and other locoregional complications than those reported following sentinel lymph node surgery. Neoadjuvant therapy, particularly chemotherapy in patients with more aggressive breast cancer subtypes, often converts cN1 patients to pathologically node negative (ypN0), and studies with neoadjuvant chemotherapy suggest that many such patients can be effectively managed with limited lymph node removal with sentinel lymph node surgery alone or with resection of the biopsy-proven node (targeted axillary dissection) and, as a result, will have much lower rates of lymphedema and other complications. (See 'Positive axilla prior to treatment' below.)

●Patients with temporary contraindications for surgery – Neoadjuvant systemic therapy is a treatment option for patients who have medical contraindications to undergoing surgery at diagnosis but in whom surgery is anticipated at a later date, such as women with breast cancer diagnosed during pregnancy or patients requiring short-term anticoagulation such as those with recent pulmonary embolism, deep-vein thrombosis, or placement of drug-eluding coronary stents. Additionally, during the COVID-19 pandemic, when access to operating rooms was limited, use of neoadjuvant endocrine therapy was increased for patients with hormone receptor-positive, HER2-negative breast cancer [23,24]. (See "Gestational breast cancer: Treatment", section on 'Systemic therapy'.)

PRETREATMENT EVALUATION — Pretreatment evaluation is aimed at confirming pathology and documenting the extent of the disease.

Tumor evaluation — As with all patients presenting with a new diagnosis of breast cancer, histopathologic confirmation and evaluation of receptor status (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) must be obtained before initiating treatment. A radiopaque clip should be placed in the tumor (or several clips in the setting of multifocal or multicentric disease), either at the time of the diagnostic biopsy or at some other time prior to initiation of neoadjuvant therapy. The clip allows for identification of the site of disease to guide surgical resection after neoadjuvant therapy as well as directing pathologic assessment of the surgical specimen, especially in cases in which neoadjuvant therapy significantly shrinks or eradicates the tumor. (See "Breast biopsy", section on 'Clip placement'.)

Imaging — Imaging should be performed prior to neoadjuvant therapy to document the extent of the disease. In many cases, ultrasound (US) of the breast is sufficient to document tumor size. However, breast magnetic resonance imaging (MRI) may be helpful to evaluate disease extent, including assessing for the presence of multifocal or multicentric disease, especially in patients with dense breast tissue on mammography; possible spread to deep axillary, subpectoral, or internal mammary lymph nodes; or invasion of the underlying chest wall. The benefits of detecting more extensive involvement in the ipsilateral breast and/or potential additional sites of pathology in either breast with MRI must be weighed against the risks of false-positive or clinically insignificant findings that might cause a patient who is a candidate for breast conservation to decide to undergo unilateral, or even bilateral, mastectomy. Retrospective analyses have demonstrated no improvement in outcomes and higher mastectomy rates in patients undergoing pretreatment MRI. (See "MRI of the breast and emerging technologies", section on 'Preoperative evaluation of newly diagnosed breast cancer patients'.)

While the presence of overt metastatic disease would alter the patient's treatment plan and goals, the likelihood of detecting it, in the absence of suspicious symptoms or findings, with routine imaging studies such as computed tomography (CT), bone, and/or positron emission tomography (PET)/CT scans, is low. To avoid the unnecessary expense of these tests and the complications of dealing with false-positive findings, we typically omit them in patients with clinical stage I or II disease but order them in patients with clinical stage III disease or inflammatory breast cancers, as well as in patients with symptoms or abnormal findings (including laboratory values) that might be an indication of otherwise occult metastatic disease. (See "Clinical features, diagnosis, and staging of newly diagnosed breast cancer", section on 'Staging'.)

Node evaluation — cN1 disease includes patients with clinically palpable axillary nodes and those with sonographically detected axillary nodal disease with pathologic confirmation of axillary metastasis identified by fine needle aspiration (FNA) or core needle biopsy (CNB). Of note, the number of abnormal appearing nodes on axillary US or MRI does not impact the cN stage. cN2 disease requires fixed or matted axillary nodes on examination.

To assess nodal status, we perform a physical exam of the axilla in all patients with a new diagnosis of breast cancer. For those in whom lymph nodes are palpated, we perform US-guided FNA or CNB to confirm pathologic involvement. The aspiration or biopsy is done to rule out a false-positive clinical finding due to reactive lymph nodes or other benign histology.

For those in whom no abnormal lymph nodes can be palpated, we routinely obtain an axillary US. If no abnormal lymph nodes are identified, we proceed with neoadjuvant treatment. If there are any suspicious lymph nodes on US (based on size or the presence of a thickened cortex), we perform FNA or CNB of the suspicious lymph node. If positive, this is categorized as cN1 disease. While there are false-negative results with either FNA or CNB (20 to 25 percent for FNA, and slightly lower for CNB), a positive sample, in a patient previously considered node negative, will allow more appropriate treatment planning, especially as it relates to surgical management of the axilla after neoadjuvant therapy. (See 'Positive axilla prior to treatment' below.)

In a patient with a positive FNA or CNB, we favor placement of a radiopaque clip or other marker (eg, ink) in the biopsy-proven involved lymph node to enable identification after neoadjuvant therapy. In patients with node-positive disease at presentation, removal of the marked node at the time of post-neoadjuvant therapy sentinel lymph node biopsy (SLNB) lowers the false-negative rate (1.4 versus 10.1 percent with SLNB alone, in one prospective study) [25,26]. The marked node will be identified as one of the SLNs in 73 to 77 percent of cases [25-27]; preoperative localization of the marked node can increase the likelihood that it is removed during SLN surgery.

While some specialists favor pretreatment SLNB for those without evidence of lymph node involvement on exam or imaging, we typically defer this until after neoadjuvant treatment. This avoids an additional surgical procedure and preserves the prognostic information obtained from the status of the nodes after neoadjuvant therapy [14]. Although it is not our preferred approach, the management of patients with clinically negative axillary exams who undergo a pretreatment SLNB is discussed below. Resection of a positive SLN prior to neoadjuvant therapy means that pathologic assessment of response after therapy is not complete, as axillary response cannot be known given the SLN was removed. Hence, SLN surgery prior to systemic therapy is discouraged. (See 'Those with SLNB prior to treatment' below.)

NEOADJUVANT TREATMENT OPTIONS — Chemotherapy remains the standard neoadjuvant approach in most patients, in particular those with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as well as in locally advanced hormone receptor-positive/HER2-negative disease. The choice between chemotherapy and endocrine neoadjuvant therapy in hormone receptor-positive disease is discussed in detail elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer", section on 'Therapeutic options'.)

Neoadjuvant chemotherapy (NACT) for those with HER2-negative cancers is discussed in detail elsewhere. (See "Choice of neoadjuvant chemotherapy for HER2-negative breast cancer".)

Patients with HER2-positive cancers should also receive one or more HER2-targeted agents, concurrent with all or some of their NACT. Chemotherapeutic regimens and targeted therapies for such patients are discussed in detail elsewhere. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Chemotherapy'.)

POST-TREATMENT EVALUATION AND MANAGEMENT — One of the primary objectives of neoadjuvant therapy is to improve surgical outcomes for patients with newly diagnosed breast cancer. We recommend proceeding with definitive surgery as soon as the patient has recovered from the toxicities of neoadjuvant treatment, usually within three to six weeks.

Clinical assessment and indications for imaging — Once a patient has completed neoadjuvant therapy, physical examination and imaging studies should be performed to assess response to treatment. The imaging modality that most clearly demonstrated the extent of disease at presentation is likely to be the most informative after neoadjuvant treatment. On the other hand, considerations for surgical planning may dictate the decision as to whether to obtain post-treatment studies and the type of imaging performed. For example, repeat breast imaging after neoadjuvant therapy may not be necessary in patients with multicentric disease, extensive calcifications, or other clear contraindications to breast-conserving therapy (BCT), or in patients who have decided to undergo mastectomy even if they are candidates for BCT.

Even in patients with a clinical complete response to neoadjuvant therapy, no standard imaging modality can exclude the presence of residual invasive disease, as the correlation between tumor measurements by physical examination, imaging (mammography, ultrasound [US], or magnetic resonance imaging [MRI]), and tumor size on final pathologic analysis is modest [28-36]. This lack of concordance may be due to the variable patterns of tumor response to neoadjuvant treatment, which range from symmetric shrinkage around a central core (which may contain residual cancer or fibrotic tissue) to apparent complete resolution of a discrete mass despite persistence of microscopic foci of invasive cancer. Thus, surgical resection remains the standard of care even in the setting of clinical complete and imaging response.

Positron emission tomography (PET) scans (fluoro-2-deoxyglucose PET [FDG-PET]) are not sufficiently sensitive for detecting residual disease to be used in routine assessment of the impact of neoadjuvant therapy [37,38] and are not routinely recommended following neoadjuvant therapy unless there is concern for the development of distant metastases.

Management of the axilla — For women who have received neoadjuvant therapy, our approach to the axilla depends on the presence of suspicious nodes prior to neoadjuvant therapy (either on exam or axillary US), the results of a fine needle aspiration (FNA) or core needle biopsy (CNB) of such nodes prior to treatment, and clinical node status following neoadjuvant therapy (algorithm 1). Although discouraged, if a patient underwent sentinel lymph node biopsy (SLNB) prior to neoadjuvant therapy, the results from that analysis also impact post-neoadjuvant therapy management of the axilla. (See 'Those with SLNB prior to treatment' below.)

Clinically negative axilla prior to treatment (no pretreatment SLNB) — Patients with no evidence of lymph node involvement prior to or during neoadjuvant therapy, or those who had negative needle biopsies of any suspicious nodes at diagnosis, should undergo sentinel lymph node biopsy (SLNB) following completion of neoadjuvant therapy. The management of the small fraction of patients who develop clinically positive axillae during treatment as well as those who underwent a pretreatment SLNB is discussed elsewhere. (See 'Poor response to or progression on neoadjuvant therapy' below and 'Those with SLNB prior to treatment' below.)

Data in support of performing an SLNB after neoadjuvant therapy include a meta-analysis of 16 studies encompassing 1456 women with clinically node-negative breast cancer who underwent SLNB and axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NACT). In this population, the sentinel node identification rate was 96 percent and the false-negative rate (FNR) was 6 percent [39].

For patients undergoing a post-treatment SLNB, our approach is to perform it concurrently with breast surgery. Patients should be advised that an ALND may be performed at the same time if intraoperative analysis, usually by frozen section, demonstrates persistent disease in the sampled nodes, and that if results of the final SLNB pathology differ from the intraoperative findings, subsequent axillary surgery may be recommended.

●If the SLNB post-treatment is negative (ypN0), no further axillary treatment is required.

●If the SLNB post-treatment is positive (ypN+), we suggest proceeding with ALND (algorithm 1). For patients keen to avoid ALND, axillary radiation may be considered as an alternative, with appropriate counseling that the equivalence of this approach in terms of locoregional disease control has not been demonstrated.

●Patients in whom sentinel node mapping is not technically successful require an ALND.

Positive axilla prior to treatment — For patients with confirmed involvement of the axilla on FNA or CNB obtained prior to treatment, and for those in whom clinical suspicion of nodal involvement was high but histologic confirmation was not obtained, management of the axilla involves sentinel node surgery, ALND, and/or axillary radiation. A choice between them depends on the extent of nodal involvement prior to neoadjuvant therapy and, for those with limited involvement (cN1), response to treatment (algorithm 1).

For those with evidence of extensive nodal involvement (cN2 or cN3 (table 1)) prior to treatment, an ALND should be performed following neoadjuvant therapy, independent of the clinical response to treatment, with subsequent regional nodal irradiation. The rationale for these interventions is discussed in detail elsewhere. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Initial cN2 or cN3 disease, or clinically node positive after neoadjuvant therapy' and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients who received neoadjuvant therapy'.)

For those with clinical N1 disease (preferably with FNA or CNB confirmation of a positive node, and the absence of fixed or matted nodes [cN2] on clinical examination (table 1)) prior to treatment, management depends on the response to neoadjuvant therapy:

●Patients with a persistent clinically positive axilla (ycN1) after neoadjuvant therapy should undergo an ALND. For patients with residual nodal disease following neoadjuvant therapy, nodal radiation following ALND is also offered. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Involved lymph nodes'.)

●Patients who are clinically node negative after neoadjuvant therapy (ycN0) should be considered for SLNB and resection of the node that was positive by FNA or CNB at baseline (this is the rationale for marking this node with a clip or other identifying marker). (See 'Node evaluation' above.)

Some UpToDate contributors obtain axillary US post-neoadjuvant therapy, prior to surgery, to assess the appearance of the axillary nodes. Limiting SLNB to patients with a normal nodal exam by US and pursuing ALND in those with sonographically abnormal lymph nodes has been shown to decrease the FNR associated with SLNB (defined as the frequency with which patients with negative sentinel nodes were found to have metastatic disease in nonsentinel axillary nodes on subsequent ALND). The ACOSOG Z1071 trial evaluated the accuracy of axillary US in 611 patients who presented with cN1 or cN2 disease and underwent US, SLNB, and ALND following NACT [40]. The major findings were that patients with suspicious nodes on post-NACT US were very likely to have positive nodes at surgery (72 percent) and to have a greater number of positive nodes and larger nodal metastases than patients with normal-appearing nodes. Limiting SLNB to patients with a normal US and pursuing ALND in patients with abnormal US reduced the FNR of SLNB (when at least two sentinel nodes are sampled) from 13 to 10 percent.

On the other hand, it is recognized that the use of clips or other methods to mark the index-positive node and ensuring that the marked node is removed at surgery further reduces the false-negative rate [41]. As such, other UpToDate contributors do not obtain a post-neoadjuvant therapy axillary US in cN1 patients who are clinically node negative after treatment (ycN0), and typically offer these patients SLNB, with subsequent management determined by intraoperative or postoperative pathologic assessment of the nodes obtained during surgery.

Based on these results, our approach is as follows (algorithm 1):

●If a post-treatment US is obtained and it shows findings concerning for persistent residual nodal disease (eg, one or more grossly involved lymph nodes), ALND should be performed, which may be done at the time of breast surgery. Patients with residual nodal involvement following neoadjuvant therapy typically receive regional nodal irradiation after ALND. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Indications for regional nodal irradiation'.)

●If a post-treatment US is not obtained, or if it is obtained and the axillary nodes are normal or improved but not completely normalized in appearance, post-treatment SLNB as well as removal of the node that was positive by FNA or CNB should be planned, which is referred to as a targeted axillary dissection. This may be performed at the time of breast surgery, with intraoperative assessment of the sampled nodes, if possible, with subsequent management determined by intraoperative or postoperative pathologic assessment of these nodes.

When performing SLN surgery after neoadjuvant therapy in patients with cN1 disease and a biopsy-proven positive lymph node, methods to decrease the FNR include use of dual tracer (radiotracer and blue dye), preoperative localization of the clipped or otherwise marked node to ensure resection of that node, resection of at least two sentinel lymph nodes, and use of immunohistochemical staining on the SLNs [42].

Approach to results of SLNB in this setting is as follows:

•If one or more of the sentinel lymph nodes are pathologically involved (ypN+), if a nonsentinel lymph node is involved, or if no SLNs are identified, ALND is the standard approach (although clinical trials are assessing whether axillary radiation therapy [RT] could be used in place of ALND).

•In cN1 patients with a negative SLNB post-neoadjuvant therapy (ypN0), an ALND can usually be avoided [43], given such patients have excellent disease-free and overall survival outcomes [44]. If two SLNs are recovered, or if only one SLN is recovered but that is the marked node [45], we forego ALND. Usually, we proceed with axillary radiation (though the necessity of this treatment is also being assessed by ongoing trials). However, for patients with one negative SLN that does not contain a clip or other marker or biopsy site changes, optimal management is unclear, given the higher likelihood of a false-negative SLNB [46,47]. In such situations, the risks and benefits of an ALND versus axillary RT alone must be discussed with the patient, since there remains uncertainty as to whether axillary RT is equivalent to ALND in terms of regional control in this setting.

Breast surgery — Whether a patient is eligible for breast-conserving surgery after neoadjuvant therapy is dependent on the extent of tumor involvement after treatment. Breast conservation is not recommended for multicentric disease. Indications for mastectomy are discussed elsewhere. (See "Overview of breast reconstruction" and "Mastectomy" and "Breast-conserving therapy", section on 'Patient selection for BCT'.)

Pathologic assessment — Pathologic assessment of the breast and axillary nodes (except in patients with a negative SLNB prior to their neoadjuvant therapy) is performed to determine the presence and extent of residual invasive disease after completion of neoadjuvant treatment.

Assessment for pathologic complete response — Achievement of pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) correlates with improved survival [48,49]. This correlation has been shown to be greatest in triple-negative breast cancer (TNBC), followed by human epidermal growth factor receptor 2 (HER2)-positive breast cancer [18,50]. Patients with estrogen receptor (ER)-positive breast cancers rarely achieve a pCR with neoadjuvant endocrine therapy, and therefore, attempts have been made to quantitate response. Available tools are discussed in detail elsewhere. (See "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)

The CTNeoBC pooled analysis of neoadjuvant breast cancer trials with mature follow-up aimed to characterize the relationship between pCR and long-term outcomes. A total of 11,955 patients were included in the study. Achieving a pCR in the breast and the axilla (ypT0 ypN0 or ypT0/is ypN0) was associated with improved event-free survival (EFS) and overall survival (OS) compared with a pCR in the breast alone. When analyzed by tumor subtype, the association between pCR and outcomes was greatest in more aggressive subtypes (in patients with TNBC, EFS hazard ratio [HR] 0.24, 95% CI 0.18-0.33, and OS HR 0.16, 95% CI 0.11-0.25; in patients with HER2-positive/hormone receptor-negative breast cancer who received trastuzumab, EFS HR 0.15, 95% CI 0.09-0.27, and OS HR 0.08, 95% CI 0.03-0.22). When a pCR was achieved, the risk of death was reduced by 84 percent for TNBC, 92 percent for HER2-positive/hormone receptor-negative breast cancer treated with trastuzumab, and 71 percent for grade 3 hormone receptor-positive/HER2-negative breast cancer [50,51]. Similarly, in results from I-SPY2, pCR was associated with EFS and distant recurrence-free survival (DRFS) for all subtypes of breast cancer [52].

Residual cancer burden — The residual cancer burden (RCB) calculator provides a standardized approach for assessing the extent of residual invasive disease in the tumor bed and axillary nodes after NACT [53,54]. Scores calculated using this tool were shown to be predictive of relapse-free survival at 10 years, and when broken down into four classes (RCB-0, which is essentially synonymous with pCR, RCB-I, RCB-II, and RCB-III) can be used to stratify risk of recurrence by extent of residual disease.

A recent pooled analysis including 5161 patients demonstrated that RCB was predictive of both EFS and DRFS in both the overall patient population and in each of four breast cancer subtypes (triple-negative, hormone receptor-negative/HER2-positive, hormone receptor-positive/HER2-positive, and hormone receptor-positive/HER2-negative), even when the results were adjusted for variables including age, tumor grade, pretreatment breast tumor size, and nodal involvement, [55]. However, the magnitude of the impact of an increase in RCB score on these endpoints differed slightly between subtypes. While prior analyses suggested that there was little difference in prognosis between patients who achieved pCR and those with minimal residual disease (RCB-0 and RCB-I, respectively), in this larger analysis there was a notable difference in outcomes between these groups except among patients with hormone receptor-positive/HER2-negative cancers. Using RCB or other methods to estimate a patient's risk of recurrence after NACT may help to guide the selection of subsequent systemic therapy.

Other evaluations such as assessing the presence and prevalence of tumor-infiltrating lymphocytes have been proposed as prognostic tools [56], but validation in clinical trials is necessary.

No role for routinely retesting receptors — For patients with residual invasive disease at surgery, we do not routinely retest ER, progesterone receptor (PR), and HER2 on the surgical specimen. While discordance in ER, PR, and HER2 receptors between the initial tumor biopsy and tissue obtained at surgery has been reported, it is not known whether this is a sampling effect or modulation of expression as a direct result of neoadjuvant treatment [57], and there is no evidence that adjuvant (postoperative) treatment decisions should be influenced by the status of the receptors following neoadjuvant therapy. Thus, until data become available, we base adjuvant treatment decisions on pretreatment tumor receptor status. However, some centers favor retesting residual disease after NACT in patients with hormone receptor-negative cancers for ER and PR to determine if the patient should be offered adjuvant endocrine therapy; there are no data supporting or refuting such an approach.

ADJUVANT TREATMENT — The general approach for patients who have received neoadjuvant treatment is discussed below, with further details discussed elsewhere.

●For most patients who receive neoadjuvant therapy, the indications for postoperative (adjuvant) radiation therapy are dependent on the pretreatment stage and type of surgery, and, increasingly, take into consideration response to neoadjuvant therapy. These issues are discussed in detail elsewhere:

•For those proceeding with breast-conserving therapy: (see "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients who received neoadjuvant therapy').

•Decisions regarding adjuvant RT are discussed in detail elsewhere: (see "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer").

●For patients with hormone receptor-positive disease, adjuvant endocrine therapy is administered. This may include ovarian function suppression or ablation in higher-risk premenopausal women, especially younger women (age <35 years) and those with evidence of recovery of ovarian function after neoadjuvant chemotherapy (NACT). (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer".)

●In patients with triple-negative breast cancer who received a full course of NACT but are found to have more than minimal residual invasive disease in the breast or lymph nodes, the potential benefit of administration of additional chemotherapy is discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Patients who received neoadjuvant treatment'.)

●In patients with human epidermal growth factor receptor 2 (HER2)-positive disease who completed all planned neoadjuvant therapy, including chemotherapy and single- or dual-HER2-targeted therapy, but are found to have more than minimal residual invasive disease in the breast or lymph nodes, the approach to adjuvant treatment is discussed in detail elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Patients who were treated with neoadjuvant therapy'.)

SPECIAL CONSIDERATIONS

Those with SLNB prior to treatment — Some centers prefer to obtain a sentinel lymph node biopsy (SLNB) in patients with clinically negative axillae prior to neoadjuvant therapy. Of note, if a positive sentinel lymph node is resected prior to neoadjuvant therapy, it is not possible to ascertain after neoadjuvant therapy whether the patient had a complete response to treatment, which limits its usefulness to guide adjuvant therapy recommendations. While we obtain SLNB after neoadjuvant therapy for reasons discussed above, pretreatment SLNB is discussed below.

Axillary management decisions for patients who undergo SLNB prior to neoadjuvant therapy are based upon the results of that SLNB.

●If the SLNB was negative (pN0), no further axillary evaluation or treatment is required, either prior to or post-neoadjuvant therapy.

●If one or more pathologically involved sentinel or nonsentinel nodes were found on the preneoadjuvant therapy SLNB, a repeat SLNB after neoadjuvant therapy should not be performed. Axillary lymph node dissection (ALND) is recommended and should be performed after neoadjuvant therapy. Note that even if all additional axillary nodes obtained on ALND performed after neoadjuvant therapy are negative, this should not be considered an axillary complete response.

•Decisions regarding adjuvant RT are discussed in detail elsewhere, both for those who proceed with breast-conserving therapy (BCT) and for those who undergo mastectomy after neoadjuvant:

-For those proceeding with BCT: (see "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients who received neoadjuvant therapy').

-For those proceeding with mastectomy: (see "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer").

Poor response to or progression on neoadjuvant therapy — Less than 5 percent of patients will have tumor progression during neoadjuvant chemotherapy. For patients who experience progression during neoadjuvant treatment, and who are operable with either mastectomy or lumpectomy, we typically stop therapy and proceed with surgical management or transition to another systemic therapy regimen. Surgical management may include axillary lymph node dissection for those with clinically positive axillae (cN1 to 3) prior to treatment or the rare cN0 patient who develops evidence of nodal involvement during neoadjuvant therapy. Indications for mastectomy after neoadjuvant treatment are the same as for patients who did not receive neoadjuvant therapy and are discussed elsewhere. (See "Overview of breast reconstruction" and "Mastectomy" and "Breast-conserving therapy", section on 'Patient selection for BCT'.)

Patients who remain inoperable may proceed with next-line chemotherapy in order to try to reduce the tumor mass and create the opportunity for definitive locoregional management with surgery and radiation treatment. Patients who develop metastatic disease during neoadjuvant therapy are treated as appropriate for stage IV disease with their tumor subtype and extent of disease. (See "Overview of the approach to metastatic breast cancer".)

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Rationale – Neoadjuvant therapy refers to the systemic treatment of breast cancer prior to definitive surgical therapy (ie, preoperative therapy). While all systemic therapy given for non-metastatic invasive breast cancer is intended to reduce the risk of distant recurrence, the purpose of administering it neoadjuvantly is to try to downstage the cancer, allowing for less extensive surgery, improved cosmetic outcomes, and reduced postoperative complications such as lymphedema, and to assess the response to treatment. (See 'Goals' above.)

●Candidates – Potential candidates for neoadjuvant therapy include those with locally advanced breast cancers, those who desire breast-conserving surgery but are not candidates or could have an improved cosmetic outcome from breast-conserving surgery if the size of the breast tumor were reduced, patients with ipsilateral axillary lymph node involvement, and those with biologically aggressive subtypes, such as triple-negative or human epidermal growth factor receptor 2-positive breast cancer, in whom response to neoadjuvant therapy could influence selection of adjuvant therapy, among others. (See 'Patient selection' above.)

●Pretreatment evaluation

•We perform a physical exam and ultrasound on the axilla for all patients with a new diagnosis of invasive breast cancer in whom neoadjuvant therapy is being considered, with subsequent fine needle aspiration or core needle biopsy of suspicious nodes. For those with a positive biopsy result, we favor placement of a radiopaque clip or other marker in the involved lymph node to mark it in case it is no longer prominent after neoadjuvant therapy. (See 'Node evaluation' above.)

•While some centers pursue pretreatment sentinel lymph node biopsy (SLNB) for those without evidence of lymph node involvement on exam or imaging, we perform axillary surgery after neoadjuvant treatment. This avoids an additional surgical procedure and preserves the prognostic information obtained from response in the nodes following neoadjuvant therapy. (See 'Node evaluation' above.)

●Post-treatment evaluation and management – Once a patient has completed neoadjuvant therapy, physical exam and imaging are performed for assessment of tumor response and surgical planning. Our approach to management of the axilla in patients receiving neoadjuvant therapy is summarized in the algorithm (algorithm 1).

•cN0 disease – Patients with no evidence of lymph node involvement prior to or during neoadjuvant therapy should proceed with SLNB following neoadjuvant therapy (provided it has not already been performed), with decision for further axillary management dependent on the pathologic findings in the nodes obtained with that procedure. (See 'Clinically negative axilla prior to treatment (no pretreatment SLNB)' above.)

●cN1 disease with a good response to neoadjuvant treatment – For patients with cN1 disease who have a good clinical and imaging response to neoadjuvant therapy (ycN0), some UpToDate authors obtain an axillary ultrasound (US), while others do not. (See 'Positive axilla prior to treatment' above.)

-If a post-treatment axillary US is obtained and shows persistent residual nodal disease (eg, several grossly involved lymph nodes), we suggest axillary lymph node dissection (ALND), rather than SLNB (Grade 2C), which may be done at the time of breast surgery. Patients with residual nodal involvement typically receive regional nodal irradiation after ALND. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients who received neoadjuvant therapy'.)

-If a post-treatment US is not obtained, or if it is obtained and the axillary nodes are normal or improved but not completely normalized in appearance, post-treatment SLNB with a dual tracer should be performed, along with removal of the marked node.

-If one or more of the sentinel lymph nodes are pathologically involved (ypN+), if a nonsentinel lymph node is involved, or if no sentinel lymph nodes are identified, we suggest ALND (Grade 2C) rather than no further axillary surgery.

-In most cN1 patients with negative SLNB post-neoadjuvant therapy (ypN0), we suggest no ALND (Grade 2C), particularly if at least two sentinel nodes are removed, and the patient is planning to receive axillary radiation therapy. Similarly, an ALND can usually be avoided in patients with a single negative sentinel node (ypN0) resected that contains the clip or other marker. However, for those patients who have only one sentinel lymph node without a clip identifier, the optimal management is unclear, and an ALND may be preferable, depending on patient values and preferences.

•More extensive disease or poor response to neoadjuvant treatment – For patients with either:

-Baseline extensive nodal disease (cN2 or cN3 (table 1)), irrespective of response to neoadjuvant treatment, or

-Baseline cN1 disease with a persistent clinically positive axilla after neoadjuvant therapy (ycN1),

We suggest ALND (Grade 2C). Patients with residual nodal involvement typically receive regional nodal irradiation after ALND. (See 'Positive axilla prior to treatment' above and "Overview of management of the regional lymph nodes in breast cancer", section on 'Initial cN2 or cN3 disease, or clinically node positive after neoadjuvant therapy' and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Patients who received neoadjuvant therapy'.)

●Choice of breast surgery after treatment – Whether a patient is eligible for breast-conserving surgery after neoadjuvant therapy takes into consideration the extent of tumor involvement pre- and post-treatment. Indications for mastectomy are discussed elsewhere. (See 'Breast surgery' above.)

●Special considerations for patients with progression on treatment – For patients who experience progression during neoadjuvant treatment, and who are operable with either mastectomy or lumpectomy, we either switch therapy or stop therapy and proceed directly with surgical management. Patients who remain inoperable should consider next-line chemotherapy in order to reduce the tumor mass and create opportunities for surgery and radiation treatment. Patients who develop metastatic disease during neoadjuvant therapy are treated as appropriate for stage IV disease with their tumor subtype and extent of disease. (See 'Poor response to or progression on neoadjuvant therapy' above.)